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EGCG Stabilizes p27^kip1 in E2-Stimulated MCF-7 Cells through Down-Regulation of the Skp2 Protein

Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan 100

Address all correspondence and requests for reprints to: Jen-Kun Lin, Ph.D., Institute of Biochemistry and Molecular Biology, National Taiwan University Medicine College, Room 947, No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan. E-mail: jklin{at}ha.mc.ntu.edu.tw.

Loss of p27^Kip1 is associated with a poor prognosis in breast cancer. According to previous findings, a decrease in p27^Kip1 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S-phase kinase protein 2 (Skp2). Epigallocatechin-3-gallate (EGCG), the main constituent of green tea, was found to stabilize p27^Kip1 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression remains unclear. Here we investigated the mechanisms involved in EGCG’s growth inhibition of estrogen-responsive human breast cancer MCF-7 cells. In our results, EGCG increased p27^Kip1 and decreased Skp2 in a time- and dose-dependent manner, suggesting that p27^Kip1 and Skp2 may be involved in the growth inhibition by EGCG in estrogen-stimulated MCF-7 cells. Interestingly, mRNA levels of p27^Kip1 and Skp2 did not significantly change in estrogen-stimulated MCF-7 cells after EGCG treatments. Moreover, overexpression of Skp2 in MCF-7 cells prevented accumulation of p27^Kip1 and promoted resistance to the antiproliferative effects of EGCG. This suggests that the down-regulation of the F-box protein Skp2 is the mechanism underlying p27^Kip1 accumulation. Furthermore, both tamoxifen and paclitaxel significantly and synergistically enhanced the growth inhibition of MCF-7 cells by EGCG through the down-regulation of Skp2 protein. However, the down-regulation of Skp2 was not always correlate with the up-regulation of p27, suggesting that EGCG-dependent Skp2 down-regulation can influence cell growth in several ways. The therapeutic strategies designed to reduce Skp2 may therefore play an important clinical role in treatment of breast cancer cells.